Comparable Prognosis in Different Neonatal Histidine-Tryptophan-Ketoglutarate Dosage Management
Introduction
Neonatal cardiac surgery presents unique challenges due to the physiological immaturity of organ systems, necessitating optimized myocardial protection strategies. Histidine-tryptophan-ketoglutarate (HTK) solution, initially developed by Bretschneider in the 1970s, is widely used for cardioplegia during cardiac surgeries. While established protocols recommend a single-shot perfusion of 40–60 mL/kg HTK for adult and pediatric patients, neonatal-specific guidelines remain undefined. Neonates require careful balancing of perfusion parameters—dosage, pressure, and duration—to avoid complications such as hemodilution or electrolyte imbalances. This study evaluates the safety and efficacy of high-dose (>60 mL/kg) versus standard-dose (40–60 mL/kg) HTK in neonatal on-pump cardiac surgery, focusing on short-term outcomes and myocardial protection.
Methods
Study Design and Population
A retrospective analysis included 146 neonates (≤28 days old) undergoing on-pump cardiac surgery at Fuwai Hospital (Beijing, China) between 2012 and 2018. Patients were stratified into two groups: standard-dose (SD, n = 63) and high-dose (HD, n = 83) HTK. Exclusion criteria included non-HTK cardioplegia, reoperation, heart transplantation, pre-existing renal/hepatic dysfunction, or incomplete data. Propensity score matching (PSM) adjusted for baseline differences, generating 44 matched pairs.
Surgical and Perfusion Protocols
Anesthesia and cardiopulmonary bypass (CPB) were standardized. HTK (4°C) was administered as a single shot into the aortic root. The SD group received 40–60 mL/kg, while the HD group received >60 mL/kg. Perfusion pressure was initially maintained at 80–100 mmHg, reduced to 40–60 mmHg after cardiac arrest. Modified ultrafiltration post-CPB ensured hematocrit >35% and colloid osmotic pressure of 15–18 mmHg.
Outcomes and Statistical Analysis
Primary outcomes included perioperative cardiac function (ejection fraction, enzyme release), complications, and recovery metrics (ventilation duration, ICU stay). Secondary outcomes encompassed blood product usage, electrolyte balance, and echocardiographic follow-up at 1 month, 3–6 months, and 1 year. Continuous variables were compared using t-tests or Mann-Whitney U tests; categorical variables used Chi-squared or Fisher’s exact tests.
Results
Baseline Characteristics and CPB Parameters
Before PSM, the SD group had higher weight (3.7 ± 0.4 vs. 3.4 ± 0.4 kg, P < 0.0001), shorter CPB time (123.5 [108–136] vs. 132.5 [114.8–152.5] min, P = 0.034), and lower aortic clamp time (82.9 ± 27.1 vs. 95.5 ± 26.0 min, P = 0.005). After PSM, groups were balanced in demographics, CPB duration, and complexity (RACHS-1 scores).
Myocardial Protection and Cardiac Outcomes
No significant differences were observed in post-operative cardiac enzyme levels (creatine kinase [CK], CK-MB, lactate dehydrogenase) or complications (delayed sternal closure, arrhythmias, low cardiac output syndrome). Left ventricular ejection fraction (LVEF) and end-diastolic dimensions (LVEDD) were comparable preoperatively and at discharge (Table 2). Follow-up echocardiography showed similar LVEF and LVEDD at 1 month, 3–6 months, and 1 year, except for transiently higher LVEDD in the HD group at 1 month (20.0 ± 2.8 vs. 21.5 ± 3.8 mm, P = 0.041), which normalized thereafter.
Perioperative Blood Gas and Electrolyte Profiles
Peri-CPB sodium, potassium, calcium, and hematocrit levels remained stable, with no clinically significant fluctuations (Figure 2). Glucose levels during rewarming were higher in the SD group pre-PSM (178.7 ± 49.5 vs. 153.0 ± 44.6 mg/dL, P = 0.030), but post-PSM analysis showed no differences. Magnesium levels at ICU arrival were marginally lower in the SD group (0.7 ± 0.1 vs. 0.8 ± 0.2 mmol/L, P = 0.015), though within physiological ranges.
Blood Product Utilization
Intraoperative platelet usage was higher in the SD group pre-PSM (56.6 ± 107.1 vs. 26.8 ± 25.4 mL, P = 0.034), but post-PSM revealed no differences in red blood cells, fresh frozen plasma, or platelet transfusions (Table 3).
Recovery and Extracardiac Complications
Ventilation duration (median 51 vs. 48 hours), ICU stay (5.9 vs. 4.9 days), and hospital stay (14 vs. 13 days) were comparable. Rates of pneumothorax, hydrothorax, infection, and mortality (4.5% vs. 4.5%) did not differ significantly (Table 4).
Discussion
This study demonstrates that high-dose HTK (>60 mL/kg) provides equivalent myocardial protection and clinical outcomes compared to standard dosing in neonates. The absence of significant differences in enzyme release, arrhythmias, or ventricular function aligns with prior adult and pediatric studies, suggesting HTK’s safety across age groups.
Myocardial Protection Mechanisms
HTK’s histidine buffer mitigates acidosis during ischemia, while low sodium/calcium content reduces cellular edema and calcium overload. The single-shot protocol simplifies neonatal surgery, avoiding interruptions for repeated cardioplegia. Despite higher volumes, HD perfusion did not exacerbate hemodilution, likely due to ultrafiltration and coronary sinus drainage strategies.
Electrolyte and Metabolic Considerations
Concerns about HTK-induced hyponatremia were unfounded, as sodium levels remained stable perioperatively. Glucose variability during rewarming may reflect stress responses rather than HTK-specific effects. Magnesium differences, though statistically significant, were physiologically negligible.
Clinical Implications
The comparable outcomes support flexibility in HTK dosing, particularly in complex anatomies requiring prolonged perfusion. Neonates with lower body weight or prolonged aortic clamp times may benefit from HD regimens to ensure uniform cardioplegia distribution.
Limitations and Future Directions
The retrospective design introduces potential selection bias, mitigated by PSM. Single-center data and modest sample size limit generalizability, necessitating multicenter randomized trials. Long-term neurodevelopmental outcomes were not assessed, warranting further investigation.
Conclusion
High-dose HTK (>60 mL/kg) is safe and effective for neonatal myocardial protection, with outcomes equivalent to standard dosing. This study provides critical evidence for standardizing neonatal cardioplegia protocols, emphasizing the role of perfusion pressure and volume in optimizing surgical outcomes.
doi.org/10.1097/CM9.0000000000001643
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